Project Summary: Disorders of iron metabolism, whether caused by inborn genetic errors, maladaptive responses to disease, or diet are major public health issues in the U.S. and throughout the world. Nutritional iron deficiency is associated with impaired cognitive development and reduced work output resulting in significant negative economic and social consequences. Other than iron metabolism per se, the physiological pathways involved in the adaptive cellular and organismal response to iron deficiency remain poorly defined. In addition to diet, anemia can be caused by disorders in oxygen sensing pathways associated with renal failure, normal aging, genetic mutations in hemoglobin or other proteins, and as a consequence of preterm delivery when the full switch to post-natal mechanisms of controlling erythropoietin production has not occurred. In sum, these pathological states affect millions of people in the U.S. alone. The ability to properly integrate the control of iron and oxygen metabolism is essential for optimal health throughout the life cycle. In vertebrates, iron regulatory protein 1 (IRP1) and IRP2 are central regulators of cellular iron metabolism. IRP dictate the fate of mRNA encoding proteins required for the maintenance of iron homeostasis and for the adaptive changes in response to iron status. The mRNA encoding hypoxia inducible factor 2 (HIF2), a transcription factor central to the genome wide responses to oxygen and iron, has been previously shown to be a specific target of IRP1 in cultured cells. We demonstrate that HIF2 mRNA translation is activated in IRP1-/- mice but not in IRP2-/- mice. IRP1-/- mice have profound disturbances in erythropoiesis, including a transient severe polycythemia, and display symptoms of dysregulated stress erythropoiesis. Our results to date also demonstrate that the 5' untranslated region of HIF2 mRNA contains multiple previously unrecognized putative translational regulatory elements that strongly suggest that translational control is a critical additional level at which changes in iron and oxygen level are integrated with the level of expression and action of HIF2. We propose that the IRP1-HIF2 regulatory axis is required for coordinating iron absorption and other adaptive processes with homeostatic and stress-induced erythropoiesis. Consequently, the specific aims are to determine the: 1) tissue specific roles of IRP1 deficiency in the development of polycythemia; 2) mechanisms regulating HIF2 mRNA translation by iron and oxygen. In elucidating the role of the IRP1-HIF2 axis in the adaptive and maladaptive control of central pathways of iron and oxygen metabolism our studies may ultimately have a transformative effect on the development of new therapeutic strategies for treatment of common disorders.